García-Guerrero, EstefaníaPérez-Simón, José AntonioSánchez-Abarca, Luis IgnacioDíaz-Moreno, IreneDe la Rosa, Miguel ADíaz-Quintana, Antonio2023-01-252023-01-252016-04-28http://hdl.handle.net/10668/10034Generating the immune response requires the discrimination of peptides presented by the human leukocyte antigen complex (HLA) through the T-cell receptor (TCR). However, how a single amino acid substitution in the antigen bonded to HLA affects the response of T cells remains uncertain. Hence, we used molecular dynamics computations to analyze the molecular interactions between peptides, HLA and TCR. We compared immunologically reactive complexes with non-reactive and weakly reactive complexes. MD trajectories were produced to simulate the behavior of isolated components of the various p-HLA-TCR complexes. Analysis of the fluctuations showed that p-HLA binding barely restrains TCR motions, and mainly affects the CDR3 loops. Conversely, inactive p-HLA complexes displayed significant drop in their dynamics when compared with its free versus ternary forms (p-HLA-TCR). In agreement, the free non-reactive p-HLA complexes showed a lower amount of salt bridges than the responsive ones. This resulted in differences between the electrostatic potentials of reactive and inactive p-HLA species and larger vibrational entropies in non-elicitor complexes. Analysis of the ternary p-HLA-TCR complexes also revealed a larger number of salt bridges in the responsive complexes. To summarize, our computations indicate that the affinity of each p-HLA complex towards TCR is intimately linked to both, the dynamics of its free species and its ability to form specific intermolecular salt-bridges in the ternary complexes. Of outstanding interest is the emerging concept of antigen reactivity involving its interplay with the HLA head sidechain dynamics by rearranging its salt-bridges.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Amino Acid SequenceAntigen PresentationBinding SitesHLA AntigensHumansMolecular Dynamics SimulationPeptidesProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondaryReceptors, Antigen, T-CellStatic ElectricityThermodynamicsresearch article27124285open access10.1371/journal.pone.01542191932-6203PMC4849770https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0154219&type=printablehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849770/pdf